Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens

Víneis, Paolo; Bartsch, Helmut; Caporaso, Neil E.; Harrington, Anita M.; Kadlubar, Fred F.; Landi, Maria Teresa; Malaveille, Christian; Shields, Peter G.; Skipper, Paul L.; Talaska, Glenn; Tannenbaum, Steven R.

doi:10.1038/369154a0

Cited by 243 publications

(100 citation statements)

References 10 publications

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“…Although both human NAT1 and NAT2 catalyse these reactions, human NAT2 has a three-to four-fold higher affinity than NAT1 for urinary bladder carcinogens such as 4-aminobiphenyl (ABP) and b-naphthylamine (BNA) (Hein et al, 1993b). This finding is consistent with the hypothesis that the effect of NAT2 polymorphism on urinary bladder cancer is more prevalent at low-dose aromatic amine exposures (Vineis et al, 1994(Vineis et al, , 2004.…”

Section: N-acetyltransferase Isozymes Nat1 and Nat2supporting

confidence: 79%

“…Among smokers, NAT2 slow acetylators have higher levels of 4-ABP hemoglobin adducts (Vineis et al, 1994;Yu et al, 1994;Probst-Hensch et al, 2000). Furthermore, ABP-DNA adducts in higher grade bladder tumors are found at higher levels in smokers who are slow NAT2 acetylators (Airoldi et al, 2002;Hao et al, 2004).…”

Section: Nat2 Polymorphism and Urinary Bladder Cancer Riskmentioning

confidence: 99%

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N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

2006

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A role for the N-acetyltransferase 2 (NAT2) genetic polymorphism in cancer risk has been the subject of numerous studies. Although comprehensive reviews of the NAT2 acetylation polymorphism have been published elsewhere, the objective of this paper is to briefly highlight some important features of the NAT2 acetylation polymorphism that are not universally accepted to better understand the role of NAT2 polymorphism in carcinogenic risk assessment. NAT2 slow acetylator phenotype(s) infer a consistent and robust increase in urinary bladder cancer risk following exposures to aromatic amine carcinogens. However, identification of specific carcinogens is important as the effect of NAT2 polymorphism on urinary bladder cancer differs dramatically between monoarylamines and diarylamines. Misclassifications of carcinogen exposure and NAT2 genotype/phenotype confound evidence for a real biological effect. Functional understanding of the effects of NAT2 genetic polymorphisms on metabolism and genotoxicity, tissue-specific expression and the elucidation of the molecular mechanisms responsible are critical for the interpretation of previous and future human molecular epidemiology investigations into the role of NAT2 polymorphism on cancer risk. Although associations have been reported for various cancers, this paper focuses on urinary bladder cancer, a cancer in which a role for NAT2 polymorphism was first proposed and for which evidence is accumulating that the effect is biologically significant with important public health implications.

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Section: N-acetyltransferase Isozymes Nat1 and Nat2supporting

confidence: 79%

Section: Nat2 Polymorphism and Urinary Bladder Cancer Riskmentioning

confidence: 99%

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

2006

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“…47 A "low dose effect" of passive smoking has been hypothesized, with the assumption that the effect modification by the NAT2 genotype might be amplified at low doses. 48,49 Studies have failed, however, to confirm this hypothesis 18,46 and in the Breast and Prostate Cohort consortium (BPC3), a consortium of six large prospective cohort studies including EPIC, the risk of breast cancer associated with smoking was not modified by NAT2 genotypes. 50 In conclusion, our results are consistent with an increase in breast cancer risk in women exposed to smoking, passively or actively, when compared to women never exposed to tobacco smoke during adult life.…”

Section: Epidemiologymentioning

confidence: 99%

Active and passive cigarette smoking and breast cancer risk: Results from the EPIC cohort

et al. 2014

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Recent cohort studies suggest that increased breast cancer risks were associated with longer smoking duration, higher pack‐years and a dose‐response relationship with increasing pack‐years of smoking between menarche and first full‐term pregnancy (FFTP). Studies with comprehensive quantitative life‐time measures of passive smoking suggest an association between passive smoking dose and breast cancer risk. We conducted a study within the European Prospective Investigation into Cancer and Nutrition to examine the association between passive and active smoking and risk of invasive breast cancer and possible effect modification by known breast cancer risk factors. Among the 322,988 women eligible for the study, 9,822 developed breast cancer (183,608 women with passive smoking information including 6,264 cases). When compared to women who never smoked and were not being exposed to passive smoking at home or work at the time of study registration, current, former and currently exposed passive smokers were at increased risk of breast cancer (hazard ratios (HR) [95% confidence interval (CI)] 1.16 [1.05–1.28], 1.14 [1.04–1.25] and 1.10 [1.01–1.20], respectively). Analyses exploring associations in different periods of life showed the most important increase in risk with pack‐years from menarche to FFTP (1.73 [1.29–2.32] for every increase of 20 pack‐years) while pack‐years smoked after menopause were associated with a significant decrease in breast cancer risk (HR = 0.53, 95% CI: 0.34–0.82 for every increase of 20 pack‐years). Our results provide an important replication, in the largest cohort to date, that smoking (passively or actively) increases breast cancer risk and that smoking between menarche and FFTP is particularly deleterious.

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“…The genetically based slow acetylator phenotype implies slower detoxification, i.e., higher levels of DNA adducts from arylamines, and a higher risk of bladder cancer. 9 In addition, we have hypothesized in the past that the effect of the NAT-2 genotype can be greater at low levels of exposure. 9 In other words, our hypothesis is that subjects with the slow acetylator phenotype tend to diverge from rapid acetylators more at low levels of dose than at high levels (the explanation of this phenomenon is reported below).…”

Section: Hypothesismentioning

confidence: 99%

“…9 In addition, we have hypothesized in the past that the effect of the NAT-2 genotype can be greater at low levels of exposure. 9 In other words, our hypothesis is that subjects with the slow acetylator phenotype tend to diverge from rapid acetylators more at low levels of dose than at high levels (the explanation of this phenomenon is reported below). This means that (i) there is a dose-response relationship in both rapid and slow acetylators, i.e., in both the risk increases with an increasing number of cigarettes smoked; (ii) slow acetylators in general have a greater risk of bladder cancer; (iii) the difference between slow and rapid acetylators is more evident at low doses.…”

Section: Hypothesismentioning

confidence: 99%

Dose‐response relationship in tobacco‐related cancers of bladder and lung: A biochemical interpretation

Víneis

Alavanja

Garte

2003

Intl Journal of Cancer

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The purpose of our study is to address the challenge of evaluating carcinogenic effects at low levels of exposure to carcinogens. We examine the shape of the dose-response relationship between tobacco smoking and cancers of the bladder and lung, and the implications for the evaluation of the effects of exposure at lower levels, for example, environmental tobacco smoke (ETS). DOSE-RESPONSE RELATIONSHIPS IN TOBACCO CARCINOGENESIS: BLADDER AND LUNG CANCERThe fact that low doses of tobacco may have a carcinogenic effect proportionally greater than high doses is suggested by the study of dose-response relationships. A previous study, based on the re-analysis of a multicenter case-control study on lung cancer and of several studies on bladder cancer, 1 suggested that the dose-response relationship between cigarette smoking and cancer risk tends to level off after a dose of approximately 20 -25 cigarettes/day. A few explanations were put forward to explain leveling off, including bias (less accurate reporting by heavy smokers with cancer), lower inhalation at high doses or genetic heterogeneity of the population, with a "depletion of susceptibles" at low-dose levels. To test the latter hypothesis, we have reviewed the recent studies on smoking and bladder cancer, a type of tumour that is particularly well studied from a biochemical-molecular point of view (Tables I and II).We have identified all the cohort or case-control studies on smoking and bladder cancer published from 1985 to 2002 (those published before were reviewed in the IARC Monograph on tobacco smoking 2 ). We have considered men only because data for women tended to be unstable. We have extracted dose-response data, showing odds ratios and 95% confidence intervals whenever possible. Table I shows the results of case-control studies, and Table II those of cohort studies. Virtually all studies, except 1 case-control (Momas et al., 1994) and 2 cohort studies (Engeland et al., 1996;Tulinius et al., 1997), show a leveling off after 20 -30 cigarettes/day. Engeland et al. (1996) and Tulinius et al. (1997) show an attenuation of the slope but not a clear leveling off. The consistency between the 2 different designs suggests that we are observing a real phenomenon and not an artifact because different types of bias occur in case-control and in cohort investigations. In fact, only the former design is prone to retrospective recall bias, with underestimation of heavy consumption by cancer cases.There are other examples in the literature in which the shape of the dose-response relationship levels off. The relationship between TCDD (dioxin) exposure (measured in the plasma of the exposed workers) and total mortality from cancer 3 shows a plateauing of the curve, i.e., an effect that is proportionally greater at lower levels of exposure. Other examples are liver tumours and vinyl chloride in rats 4 or lung cancer and arsenic in humans. 5 However, it should be noted that these are heterogeneous situations, concerning both mutagens like vinyl chloride and chemicals like...

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Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens

Cited by 243 publications

References 10 publications

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

Active and passive cigarette smoking and breast cancer risk: Results from the EPIC cohort

Dose‐response relationship in tobacco‐related cancers of bladder and lung: A biochemical interpretation

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